Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis

Induction of wild-type p53 in mouse fibroblasts causes cell cycle arrest at the G(1) phase, whereas coexpression of p53 and the protooncogene c-myc in duces apoptosis. Although p53 transcriptional activity generally is require d for both pathways, the molecular components mediating p53-dependent apopt osis are not well understood. To identify factors that could mediate p53-in duced cell death, we used a comparative RNA differential display procedure. We have identified Pw1/Peg3 as a gene product induced during p53/c-myc-med iated apoptosis. Pw1/Peg3 is not induced during p53-mediated G(1) growth ar rest nor by c-myc alone. Although it is not clear whether the induction of Pw1/Peg3 depends on p53 activity, we show that Pw1/Peg3 interacts with a p5 3-inducible gene product Siah1a. We demonstrate that coexpression of Pw1/Pe g3 with Siah1a induces apoptosis independently of p53 whereas expression of Pw1/Peg3 or Siah1a separately has no effect on cell death. These data sugg est that Siah1a and Pw1/Peg3 cooperate in the p53-mediated cell death pathw ay. Furthermore, we show that inhibiting Pw1/Peg3 activity blocks p53-induc ed apoptosis. The observation that Pw1/Peg3 is necessary for the p53 apopto tic response suggests a pivotal role for this gene in determining cell deat h versus survival.